DNA methylation-based biomarkers of age acceleration and all-cause death, myocardial infarction, stroke, and cancer in two cohorts: The NAS, and KORA F4
Cuicui Wang,
Wenli Ni,
Yueli Yao,
Allan Just,
Jonathan Heiss,
Yaguang Wei,
Xu Gao,
Brent A. Coull,
Anna Kosheleva,
Andrea A. Baccarelli,
Annette Peters,
Joel D. Schwartz
Affiliations
Cuicui Wang
Department of Environmental Health, Harvard T.H. Chan School of Public Health, 401 Park Drive, West of Landmark Center, Boston, MA 02215, United States; Corresponding author.
Wenli Ni
Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
Yueli Yao
Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
Allan Just
Department of Environmental Medicine, and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States
Jonathan Heiss
Department of Environmental Medicine, and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States
Yaguang Wei
Department of Environmental Health, Harvard T.H. Chan School of Public Health, 401 Park Drive, West of Landmark Center, Boston, MA 02215, United States
Xu Gao
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, United States
Brent A. Coull
Department of Environmental Health, Harvard T.H. Chan School of Public Health, 401 Park Drive, West of Landmark Center, Boston, MA 02215, United States; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
Anna Kosheleva
Department of Environmental Health, Harvard T.H. Chan School of Public Health, 401 Park Drive, West of Landmark Center, Boston, MA 02215, United States
Andrea A. Baccarelli
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, United States
Annette Peters
Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Medical Information Science, Biometry, and Epidemiology, Ludwig Maximilians University, Munich, Germany
Joel D. Schwartz
Department of Environmental Health, Harvard T.H. Chan School of Public Health, 401 Park Drive, West of Landmark Center, Boston, MA 02215, United States
Background: DNA methylation (DNAm) may play a role in age-related outcomes. It is not yet known which DNAm-based biomarkers of age acceleration (BoAA) has the strongest association with age-related endpoints. Methods: We collected the blood samples from two independent cohorts: the Normative Ageing Study, and the Cooperative Health Research in the Region of Augsburg cohort. We measured epigenome-wide DNAm level, and generated five DNAm BoAA at baseline. We used Cox proportional hazards model to analyze the relationships between BoAA and all-cause death. We applied the Fine and Gray competing risk model to estimate the risk of BoAA on myocardial infarction (MI), stroke, and cancer, accounting for death of other reasons as the competing risks. We used random-effects meta-analyses to pool the individual results, with adjustment for multiple testing. Findings: The mean chronological ages in the two cohorts were 74, and 61, respectively. Baseline GrimAgeAccel, and DNAm-related mortality risk score (DNAmRS) both had strong associations with all-cause death, MI, and stroke, independent from chronological age. For example, a one standard deviation (SD) increment in GrimAgeAccel was significantly associated with increased risk of all-cause death [hazard ratio (HR): 2.01; 95% confidence interval (CI), 1.15, 3.50], higher risk of MI (HR: 1.44; 95% CI, 1.16, 1.79), and elevated risk of stroke (HR: 1.42; 95% CI, 1.06, 1.91). There were no associations between any BoAA and cancer. Interpretation: From the public health perspective, GrimAgeAccel is the most useful tool for identifying at-risk elderly, and evaluating the efficacy of anti-aging interventions. Funding: National Institute of Environmental Health Sciences of U.S., Harvard Chan-NIEHS Center for Environmental Health, German Federal Ministry of Education and Research, and the State of Bavaria in Germany.
